Gene delivery via inhalation is a technique that shows considerable promise for the treatment and prevention of a variety of diseases, but its application has been limited by practical difficulties. In particular, safety concerns have slowed the development of some methods of aerosol gene delivery, particularly those involving viral-based systems, and the application of other delivery methods has been limited by efficiency problems. One promising approach for gene delivery involves the use of lipid-based carriers, or liposomes. However, as with other carriers, liposomes have been inefficient for nucleic acid delivery using the drug delivery devices commonly employed.
Pharmaceutical devices that have been employed for aerosol drug delivery include metered dose inhalers (MDIs), dry powder inhalers (DPIs) and air-jet nebulizers. While such devices are suitable for the delivery of some therapeutic agents, gene delivery via these devices presents practical problems. MDIs have not been used for gene delivery because of the difficulty of formulating plasmids with propellant mixtures. DPIs are also not suitable for gene delivery because a prohibitively high inspiratory air flow rate is required to achieve effective dispersion of powder blends.
Currently, the most practical pharmaceutical device for gene delivery is the air-jet nebulizer. This device uses a compressed air source to deliver a high velocity air-jet through an orifice to create a venturi effect that draws liquid from a reservoir into an air flow stream. The differential velocity between the air and the liquid causes the liquid to break up into droplets, the majority of which are in the respirable range (1-5 .mu.m). The jet nebulizer has been preferred for lipid-based gene delivery because of the comparative ease of formulation (e.g., often the parenteral formulation can be used directly), versatility in dose adjustment (concentration and frequency), affordability and time-proven delivery technology. The drug reservoir of the nebulizer can also be designed to administer high doses of aerosolized therapeutic agents to the lungs.
Significant drawbacks remain, however, with gene delivery using a jet nebulizer, including lack of portability, output variability between units, large dead volumes and variation in solution versus solvent output. The delivery efficiency (defined as the ratio of mass of drug nebulized to mass of drug deposited in the lower airways) is very low--less than 2%. This low delivery efficiency may be attributable to constant air flow through the system, resulting in continuous atomization and concomitant dilution of the output aerosol stream. Further, using a jet nebulizer, aerosols are generated even during exhalation, which accounts for 60% of the respiratory cycle.
Accordingly, there is a need in the art for improved methods of pulmonary gene delivery. The present invention fulfills these needs and further provides other related advantages.